Novel pharmaceutical composition and its use in a method for treatment of patients with upper respiratory mucosal congestion

ABSTRACT

The present invention relates to a pharmaceutical composition including loratadine or a pharmaceutically acceptable form thereof, and phenylephrine or a pharmaceutically acceptable form thereof, for treating upper respiratory/mucosal congestion, optionally by administering to a patient four times a day.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 11/922,271 filed on 20Dec. 2007 which is a national phase application from PCT/NZ2005/000132,with an international filing date and earliest priority date of 17 Jun.2005.

INTRODUCTION

The present invention relates to a pharmaceutical composition includingloratadine, its use in the treatment of upper respiratory mucosalcongestion and a method of administration of the composition.Particularly, though not exclusively, the invention relates to apharmaceutical composition including loratadine in an amount suitablefor administration a maximum of 4 times a day, and a second active thatis phenylephrine, or a salt thereof.

BACKGROUND

Upper respiratory mucosal congestion caused by infections such as thecommon cold and influenza, or allergic rhinitis, can lead to a number ofnasal and ocular symptoms. These include rhinitis and sinusitis, nasaland sinus congestion or excessive secretions, headaches, sneezing anditching and excessive lacrimation. Infections such as the common coldcan be very common over the winter months, while the symptoms ofrhinitis are also common in some parts of the world.

Such symptoms can be treated with antihistamine containing products andwith decongestant containing products. The products are generally soldas part of non-prescribed medicines which are available to patientsthrough outlets such as pharmacies.

There are a number of antihistamine actives available includingnon-sedating antihistamines such as loratadine, cetirizine orfexofenadine. These products provide less sedation in comparison tonormal antihistamines, and therefore more readily allow a user toperform tasks such as driving or operating machinery.

Fexofenadine is an active carboxylic acid metabolite of terfenadine. Thelatter has been withdrawn due to serious cardiotoxic reactions and druginteractions. In depth information regarding the risk of these reactionsis not available for fexofenadine. But according to the AHFS DrugInformation 2004 as a result of comparative studies between fexofenadineand terfenadine, it is thought that the clinical efficacy of terfenadineis attributable to fexofenadine. The risk of similar reactions toterfenadine being created by the use of fexofenadine has not been ruledout.

Cetirizine is another non-sedating antihistamine. However, in comparisonto loratadine, cetirizine has been reported to have a higher incidenceof adverse drug reactions (ADRs), especially central nervous systemADRs<1>. Some studies have also indicated that cetirizine has a higherincidence of somnolence than loratadine.

Loratadine is disclosed in U.S. Pat. No. 4,282,233 as a non-sedatingantihistamine useful as an anti-allergy agent in, for example, thetreatment of seasonal allergic rhinitis symptoms such as sneezing anditching. Loratadine has a maximum over the counter (OTC) dose of 10 mgper day. It is generally administered once a day at the maximum dose fora number of reasons including perceived efficacy and patient compliance.However, there are adverse effects that can occur at peak concentrationand also with end-of-dose diminution of effect.

There are also a number of decongestant agents available. Phenylephrinehas in the past been used as a decongestant agent. However, its use hasnow been surpassed by the next generation of decongestant productsincluding pseudoephedrine. Pseudoephedrine tends to act with a higherefficacy and has a longer half-life than previous generation productssuch as phenylephrine, providing an increase in the efficiency forrelieving symptoms.

Combination antihistamine and decongestant products are available as aresult of a demand for combination products that meet the problemsassociated with multiple product ingestion. Combinations of loratadineand new generation decongestants such as pseudoephedrine have beendisclosed with a view to administering the combination once or twice aday. Disclosure of such combinations has been made in WO 98/18470 toSchering Corporation for example.

Combinations of the older style decongestant drugs, such asphenylephrine, and sedating antihistamines are available in liquidpreparations. The use of such products has however been superseded byuse of combinations using the newer style decongestant drugs, such aspseudoephedrine, for the reasons mentioned above.

There are several solid dose products currently available which combinethe newer style drugs, such as pseudoephedrine, together withnon-sedating antihistamine. Examples of those available in Australasiaare given in Table 1 below.

TABLE 1 Current Combination Non-Sedating Antihistamine and NasalDecongestant Solid Dose Form Products Available in AustralasiaNon-sedating Product Decongestant Antihistamine Daily Dose Clarinase 12Hour Pseudoephedrine Loratadine 1 tablet twice 240 mg 5 mg dailyClarinase 24 Hour Pseudoephedrine Loratadine 1 tablet daily Relief 240mg 10 mg Demazin Pseudoephedrine Loratadine 1 tablet twice Non-Drowsy240 mg 5 mg daily Telfast Pseudoephedrine Fexofenadine 1 tablet twiceDecongestant 240 mg 60 mg daily Zyrtec Pseudoephedrine Cetirizine 1tablet twice Decongestant 240 mg 5 mg daily

However, products containing pseudoephedrine are now subject to abuseproblems associated with illicit drug use in the community. Thepseudoephedrine component of these medications can be converted topotent stimulants such as methamphetamine and methcathinone both ofwhich are CNS stimulants with great potential for habituation andphysical and/or psychic dependence. This has resulted in pharmacyhold-ups, stolen stock from warehouses and significant related crime.The resulting crime, and its effects on the outlets which supply thesemedications to the market, means that some outlets are choosing not tostock these products, or at least restrict their availability. Thismakes them less accessible to those with a genuine need for themedications. In the United States, for example, legislation restrictsthe threshold content of pseudoephedrine OTC (“over the counter”)products, for example, can contain no more than 3 g of pseudoephedrine(in terms of the base) packaged in packs of 1 or 2 dosage units per packor as package size liquid preparations.

It would be beneficial to have an alternative medication capable ofbeing available without a prescription which is effective in treatingthe symptoms of upper respiratory mucosal congestion and which mitigatesat least some of the problems identified above.

An object of the invention is to at least provide the public with auseful choice.

SUMMARY OF THE INVENTION

According to one aspect of the invention there is provided apharmaceutical composition including loratadine or a pharmaceuticallyacceptable form thereof, and phenylephrine or a pharmaceuticallyacceptable form thereof, optionally for treating upperrespiratory/mucosal congestion.

Optionally the pharmaceutical composition is for administering to apatient four times a day.

Optionally the pharmaceutically acceptable form of loratadine is a saltform of such substance.

Optionally the pharmaceutically acceptable form of phenylephrine is asalt form of such substance.

Optionally the composition is for administration on a qid basis.

Optionally the phenylephrine is present as a hydrochloride salt.

Optionally the composition is in a solid dosage form.

Optionally the composition is in the form of a pill, capsule or tablet.

Optionally the composition comprises lactose, maize starch,pregelatinised starch, quinoline yellow, sodium metabisulphite, disodiumEDTA, talc and magnesium stearate.

Optionally the composition is provided in a pack, wherein the packincludes instructions to administer the composition to a maximum of 4times a day.

According to a further aspect of the invention there is provided the useof loratadine or a pharmaceutically acceptable form thereof, andphenylephrine or a pharmaceutically acceptable form thereof, in themanufacture of a pharmaceutical composition, optionally for treatingupper respiratory/mucosal congestion.

Optionally the pharmaceutical composition is for administering to apatient four times a day.

Optionally the pharmaceutically acceptable form of loratadine is a saltform of such substance.

Optionally the pharmaceutically acceptable form of phenylephrine is asalt form of such substance.

Optionally the composition is for administration on a qid basis.

Optionally the phenylephrine is present in the composition as ahydrochloride salt.

Optionally the composition is a solid dosage form.

Optionally the composition is in the form of a pill, capsule or tablet.

Optionally lactose, maize starch, pregelatinised starch, sodiummetabisulphite, disodium EDTA, talc, and magnesium stearate are alsoused in the manufacture of the pharmaceutical composition.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

In a preferred embodiment the invention provides a method of treatingupper respiratory mucosal congestion using a pharmaceutical compositionwhich includes loratadine, preferably in amounts suitable foradministration 4 times a day, plus phenylephrine as a decongestant.

Furthermore the inventor has recognised that the selection of adecongestant that is a hydroxyl-[alpha]-[(methylamino)methyl]-benzenemethanol, or salt thereof, does not result in thedisadvantages that accrue from the selection of a decongestant that is a[alpha]-[1-(methylamino) ethyl]-benzenemethanol.

The lower efficacy and shorter half life of the selected decongestantcan be offset, at least to a limited extent, by its use in combinationwith loratadine. The advantages of this particular combination have notbefore been recognised for the compositions disclosed in thespecifications accompanying international application no. PCT/IB03/01197(Publication no. WO 03/089007) or international application no.PCT/US2003/029095 (Publication no. WO 2004/023984).

The preferred composition contains loratadine (a non-sedatingantihistamine) and phenylephrine (a decongestant). The preferredcomposition is safe to be supplied on a non-prescription basis and cantherefore be purchased over the counter (“OTC”).

TABLE 2 Dose Rates of Phenylephrine and Pseudoephedrine Agent DoseReference Phenylephrine 10 mg 3-4 times a day Martindale 28^(th) edition10 mg q 4 hours Drug Tx, 4^(th) edition Pseudoephedrine 60 mg 3-4 timesa day Martindale 28^(th) edition 60 mg qid or 120 mg bd Drug Tx, 4^(th)edition

As stated in the Martindale reference a number of suitable phenylephrinesalts can be used.

The phenylephrine component can be delivered as any suitable salt form(e.g. HCl, tartrate). The base form could also be used. Suitable saltswill be well known to the skilled person. Reference herein to the use ofphenylephrine is intended to include reference to delivery as a suitablesalt.

Loratadine has a maximum OTC daily administration of 10 mg per day. Asfor phenylephrine, suitable salts could also be used to deliver theloratadine as would be known to the skilled person. Reference herein toloratadine is intended to include administration as a suitable salt.

By way of example, it has been found that the use of about 2.5 mgloratadine administered 4 times daily (e.g. qid) has therapeuticadvantages over the usual 10 mg administered once a day. It is thoughtthat this may be due to the ideal concentration-time profile forcontinuous effect being a constant concentration over time (as wouldoccur with a continuous infusion). As the 2.5 mg loratadine use flattensout the differences between peak and trough concentrations in theplasma, this administration regime most closely resembles the effect ofa continuous infusion. The flatter concentration-time profile providesadvantages of fewer peak concentration adverse effects, and lessend-of-dose diminution of effect. Administration of the composition, interms of loratadine effect, provides distinct advantages to the user.

While the use of a combination of a non-sedating antihistamine and adecongestant is known for the treatment of upper mucosal respiratorycongestion, this previously involved the latest generation ofdecongestant medications and ordinarily involves the use of maximum OTCdoses of the actives in a single administration. Phenylephrine, anearlier generation medication, has a different potency topseudoephedrine on a milligram by milligram basis. The development ofdecongestants such as pseudoephedrine, which provide more efficientmeans of decongestion, means that the older generation of decongestants,like phenylephrine are not actives that would ordinarily be included incombination medications. The development of a loratadine plusphenylephrine product which allows the therapeutic and use advantages ofthe present invention is therefore unexpected and is a significantadvance.

The inventor has recognised that the use of an older generation drug(phenylephrine) while less efficient would, in combination with aneffective non-sedating antihistamine, still provide a helpful medicationto alleviate the symptoms of upper mucosal respiratory congestion.

Administration of the combination including phenylephrine (preferably ina suitable salt form e.g. hydrochloride, tartrate) 4 times a day (e.g.qid preferably) provides therapeutic and use advantages that mitigatethe therapeutic effect of using the older style drug while offeringadditional advantages. This enables an alternative medication to beaccessible to symptom sufferers, without restraints being placed on theavailability of this medication due to social issues resulting from theuse of the newer style drugs. In using such an older generationmedicament in combination with a non-sedating antihistamine the inventorhas also recognised the importance of minimising the potential foradverse drug reactions.

The administration of phenylephrine 4 times a day allows peak effects ofthis drug to be delivered quarterly over the day thus mitigating thefast half-life effect of phenylephrine on decongestant efficacy. It isthe combination of the preferably quarterly administration of theloratadine and the phenylephrine and the interaction of effect betweenthem, that allows the preferred pharmaceutical composition to providethe user with such a useful alternative to combinations that use newstyle decongestant drugs. Optionally, the phenylephrine could beincluded such that it is released slowly from the composition but it isnot considered that this is necessary. It may be that the combinedeffect of the two drugs when administered 4 times per day could betermed synergistic from this perspective. In the preferred embodiment itis the combination of the beneficial effects stemming from thepreferably quarterly administration of both drugs that allows the userto receive benefits over and above those provided by simplyadministering the drugs individually or in combination to meet themaximum daily dose once or twice per day. Administration for treatmentof severe symptoms is 4 times daily and as close to qid as possible.This is to maximise the advantages gained from the flat peak/troughconcentrations of the loratadine in the plasma. This allows thecomposition to provide a useful alternative to existing compositionsthat use new generation decongestants from an efficacy perspective, andprovides a composition that does not suffer from the social problemsthat hinder use of the new generation decongestants (e.g.pseudoephedrine). This combination effect (loratadine and phenylephrine)forms the basis of another, or additional, aspect of the invention.

The 2.5 mg or 2.5 mg/10 mg qid regimen does have disadvantages over theother regimens in terms of drug compliance. Once daily and twice dailyregimens are superior to qid regimens in terms of compliance. Howevercompliance is also related to the severity of symptoms, and patients areordinarily reminded to be compliant if their symptoms persist. In thiscase, non compliance when symptoms have diminished is not likely to be adisadvantage. While once or twice daily administration may havecompliance advantages, the beneficial effect of the 2.5 mg loratadine 4times a day (e.g. qid) to treat severe upper respiratory mucosalcongestion symptoms individually or together with phenylephrine is stillsignificant.

The pharmaceutical combination according to the preferred form of theinvention allows for the delivery of a total of around 10 mg loratadineand 40 mg phenylephrine per day, administered in 4 doses. Thepharmaceutical composition may include loratadine in an amount of about2.5 mg and phenylephrine (preferably as the hydrochloride salt) in anamount of about 10 mg. The amount of actives used in the compositionwill of course be within the margins of error allowed for pharmaceuticaluse.

The preferred compositions also include non-active components such asbinders and other excipients as would be known by a person skilled inthe art. The ingredients can be formulated into a tablet, pill orcapsule using known pharmaceutical carriers and excipients (such asdiluents, binders, colourants, antioxidants, chelating agents, glidantsand/or lubricants). The composition is formulated into a tablet of asize capable of containing the amounts of ingredient preferred.Preferably the composition is manufactured using pharmaceuticallyacceptable ingredients as would be known to the skilled person, such asmaize or pre-gelatinised starch, lactose (e.g. monohydrate)microcrystalline cellulose, magnesium stearate, quinoline yellow, sodiummetabisulphite, EDTA, talc.

Purified water will preferably be used. As will be appreciated bypersons skilled in the art, purified water may be used during theformulation process, which includes a drying process. The drying processevaporates the water from the composition, meaning that the water doesnot contribute to the final weight of the composition.

The tablets/pills will preferably be presented to the consumer as partof a pharmaceutical pack, such as a blister pack, as will be well known.The pack should have an even number of pills contained within it andhave instructions about the maximum number of pills/tablets to be takenat any one time and within a set timeframe. In the present case, onetablet/pill/capsule should be taken 4 times per day (preferably qid). Itis of course possible that the pills/tablets/capsules could be soldcontained in a bottle, the pills held loosely within that bottle. Again,instructions on administration 4 times daily (preferably qid) would beincluded.

In a further alternate embodiment the pharmaceutical composition can bea syrup for administration to children, and patients with difficultyswallowing pills. Standard methods for the production of such syrups arewell known in the art. The syrup may be contained in a bottle, vial orlike container and prepared in a manner capable of delivering about 2.5mg loratadine, and preferably about 10 mg phenylephrine per dose, 4times daily. This would be achievable by producing a syrup having aspecified concentration of the actives, in conjunction with instructionsabout how much of the syrup should be taken per quarterly dose. Withregard to doses for younger children it will be recognised that lowerdoses of such a syrup are appropriate. In respect of loratadine the dosefor children under 12 years should be less than 5 mg/day.

In some embodiments the invention can therefore be seen to be a methodof treating upper respiratory mucosal congestion in a patient in needthereof using a pharmaceutical composition including about 2.5 mgloratadine and preferably about 10 mg phenylephrine, that isadministered to a patient 4 times a day.

A preferred composition is shown in Table 3 below.

Example

The components shown in Table 3 are combined into a single tablet andtaken by either adults or children aged 12 years or older. The tabletmay be taken up to 4 times a day giving a maximum dose of 10 mg ofloratadine and 40 mg of phenylephrine per day.

TABLE 3 Combination Composition Formulation Qty. per Reference to Nameof Ingredient tablet Function specifications Active ingredient:Phenylephrine 10.00 mg Active ingredient Ph. Eur. HydrochlorideLoratadine 2.50 mg Active ingredient IHS Other Ingredients: Lactose180.40 mg Diluent Ph. Eur. Maize starch 140.00 mg Diluent, binder Ph.Eur. Pregelatinised starch 10.365 mg Binder Ph. Eur. Lake of quinoline0.20 mg Colourant IHS yellow Sodium metabisulphite 0.40 mg AntioxidantPh. Eur. Disodium EDTA 0.14 mg Chelating agent Ph. Eur. Talc 3.00 mgGlidant Ph. Eur. Magnesium stearate 3.00 mg Lubricant Ph. Eur.

The formulation administered 4 times daily provides effective 24 hourtreatment of the symptoms of upper respiratory mucosal congestion withreduced adverse effects and without using pseudoephedrine as thedecongestant.

Where in the foregoing description there has been made reference tospecific components or integers of the invention having knownequivalents then such equivalents are herein incorporated as isindividually set forth.

Although this invention has been described by way of example only andwith reference to possible embodiments thereof it is to be understoodthat modifications or improvements may be made without departing fromthe scope or spirit of the invention as defined in the accompanyingclaims.

REFERENCES

-   (1) The American Society of Health System Pharmacists Drug    Information 2004. G. K. McEvoy (Editor), Bethesda, USA

1. A pharmaceutical composition including loratadine or apharmaceutically acceptable form thereof, and phenylephrine or apharmaceutically acceptable form thereof, for treating upperrespiratory/mucosal congestion.
 2. A pharmaceutical compositionaccording to claim 1, wherein the composition is for administering to apatient four times a day.
 3. A composition according to claim 1, whereinthe pharmaceutically acceptable form of loratadine is a salt form ofsuch substance.
 4. A composition according to claim 1, wherein thepharmaceutically acceptable form of phenylephrine is a salt form of suchsubstance.
 5. A composition according to claim 1, which is foradministration on a qid basis.
 6. A composition according to claim 1,wherein the phenylephrine is present as a hydrochloride salt.
 7. Acomposition according to claim 1, which is in a solid dosage form.
 8. Apharmaceutical composition according to claim 1, which is in the form ofa pill, capsule or tablet.
 9. A pharmaceutical composition according toclaim 1, comprising lactose, maize starch, pregelatinised starch,quinoline yellow, sodium metabisulphite, disodium EDTA, talc andmagnesium stearate.
 10. A pharmaceutical composition according to claim1, having synergistic therapeutic activity.
 11. A pack including apharmaceutical composition according to claim 1, wherein the packincludes instructions to administer the composition to a maximum of 4times a day.
 12. The use of loratadine or a pharmaceutically acceptableform thereof, and phenylephrine or a pharmaceutically acceptable formthereof, in the manufacture of a pharmaceutical composition for treatingupper respiratory/mucosal congestion.
 13. A use according to claim 12,wherein the composition is for administering to a patient four times aday.
 14. A use according to claim 12, wherein the pharmaceuticallyacceptable form of loratadine is a salt form of such substance.
 15. Ause according to claim 12, wherein the pharmaceutically acceptable formof phenylephrine is a salt form of such substance.
 16. A use accordingto claim 12, wherein the pharmaceutical composition is foradministration on a qid basis.
 17. A use according to claim 12, whereinthe phenylephrine is present in the composition as a hydrochloride salt.18. A use according to claim 12, wherein the composition is a soliddosage form.
 19. A use according to claim 12, wherein the composition isin the form of a pill, capsule or tablet.
 20. A use according to claim12, wherein lactose, maize starch, pregelatinised starch, sodiummetabisulphite, disodium EDTA, talc, and magnesium stearate are alsoused in the manufacture of the pharmaceutical composition.